Osteoporosis and related bone diseases affect over 10 million Americans and result in 1.5 million fractures annually at a cost of $17-20 billion. The predominant treatment for osteoporosis is the use of drugs that block bone resorption (anti-resorptive or anti-catabolic agents). However, a primary feature of skeletal aging is a decline in the rate of bone formation, and there exists an unmet clinical need for anabolic agents to offset this decline. Tissue homeostasis, such as maintenance of bone mass, often relies on the tightly regulated activity of developmental signaling networks. Similarly, repair of injured bone or regeneration of osteopenic bone is likely to require reactivation of developmental signaling pathways. The primary objective of this proposal is to explore and elucidate the mechanisms by which Fibroblast Growth Factors (FGFs) regulate the osteoblast lineage during skeletal growth, homeostasis and aging. To manipulate regenerative response mechanisms in a beneficial way, and to restore homeostatic balance, it is essential to acquire knowledge about the normal developmental pathways and how they are reactivated and reused in adult tissues. To achieve these goals, we will investigate the mechanisms by which FGF signaling in osteoblasts regulates bone growth and homeostasis and determine if osteoblast FGF signaling can be manipulated to prevent or restore age-related bone loss. Our preliminary data supports a direct role for FGF receptor (FGFR) signaling in the osteoblast lineage in regulating bone growth and homeostasis. We show that inactivation of FGFRs in neonatal osteoprogenitor (OP) cells results in decreased skeletal growth, and inactivation of FGFRs in the adult osteoblast lineage results in loss of bone mass. We have constructed or acquired genetic tools that will allow us to control loss or gain of function of FGF signaling in adult long bone osteoblasts and in skeletal progenitor cells that give rise to chondrocytes and osteoblasts in vivo. Using these genetic tools, our goals are to: 1. Identify mechanisms for FGF regulation of osteoblast function during postnatal bone growth; 2. Identify functional consequences of loss- and gain-of- FGFR-function in the activation/maintenance of osteoblast anabolic activity for skeletal homeostasis and age- related bone loss; 3. Identify novel FGF-regulated genes and signaling pathways in the postnatal osteoblast lineage using comprehensive Next-Gen transcriptome analysis. Our multidisciplinary team brings together expertise in developmental and bone biology, bone structure and biomechanics, and genomics and bioinformatics that, combined with the genetic tools at our disposal, puts us in a unique position to address fundamental questions in the regulation of skeletal growth and homeostasis and develop new methods for effective FGF therapy to maintain or enhance bone mass during aging. PUBLIC HEALTH RELEVANCE: Osteoporosis and related bone diseases affect over 10 million Americans and result in 1.5 million fractures annually at a cost of $17-20 billion. An increased understanding of the mechanisms involved in the etiology and progression of osteoporosis is essential to improve prevention, diagnosis and treatment of bone loss and resulting skeletal fractures in an effort to reduce morbidity, mortality and the tremendous economic impact on our health care system. The Fibroblast Growth Factor signaling pathway provides an attractive therapeutic target to offset the decline in bone mass that occurs during the aging process.